TW200534860A - Multiphase product for contraception based on a natural oestrogen - Google Patents

Abstract

A multiphase product for contraception based on a natural oestrogen in combination with a synthetic progestogen, which compared with the generic conventional ovulation-inhibiting products which have proved to be reliable and safe on wide use for a long time achieves a greater contraceptive reliability over the entire duration of the cycle, improves the cyclic bleeding behaviour and controls the side effects such as breast tenderness, headaches, depressive moods and libido changes and the like.

Description

200534860 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a multiphase product for contraception based on natural estrogen and a synthetic progestin combined therewith. [Prior Art] The patent document discloses a multiphase product for contraception based on natural estrogen and a synthetic progestin combined therewith. EP"70 388 B1 describes a multiphase product for contraception - the first phase contains 2 to 4 parts per dose, and each dose unit contains natural estrogen as the sole active ingredient, first Containing 2 groups of each dose unit consisting of at least one natural estrogen and at least one synthetic or natural progesterone, wherein the first group consists of 5 to 3 wounds per day, 1 unit, and the second group Formed from 17 to 13 days per dosage unit, /, the first phase contains 2 to 4 parts per ounce unit, and each ounce unit contains the only natural estrogen as the active ingredient, /, in each phase The daily natural estrogen dosage unit is constant, but gradually decreases from the first phase to the third phase, but the proportion of synthetic or natural progesterone in the second phase of the second phase exceeds the ratio in the first group. ^8 The last phase contains 2 to 4 parts per dose, and each dose unit "is a pharmaceutically acceptable placebo for the active ingredient. The use of vapor 5 does not give estrogen valerate and diene. Nitrile composition, straight, in the first sect, not in one phase, 3 parts per A dose of 3 mg of estrogen pent 99919.doc 200534860 acid salt, in the second phase, in the first group, 4 parts per dose of 2 mg of estrogen valerate and 1 mg of diengestrolonitrile, In the second group of the second phase, there are 16 daily doses of 2 mg of estrogen valerate and 2 mg of dimethicone, and 2 parts of estrogen at a daily dose of 1 mg in the third phase. Valerate, and in the last phase, there are 3 pharmaceutically acceptable placebos per dose. For the reliability of contraception, the progesterone serum concentration is determined by radioimmunoassay, limited to 4.0 ng/ml. Progesterone. The average irregular bleeding rate (breakthrough bleeding and spot bleeding) decreased from 45% in the first taking cycle to 53% in the last taking cycle. It is also known that the contraceptive reliability of the combined product is It is derived from the effects of two components of estrogen and progesterone. It is also known that the amount of ovulation inhibitor requires 1.0 mg/day of diengestyronitrile-Dienogest: Praklinik und Klinik eines neuen Gestagens, edited by AT Teichmann, Walter de Gruyter Berlin /New York (1995) , 101 pages) and 2.0-3.0 mg drospirenone (Rosenbaum p, Schmidt W, Helmerhorst FM et al, Inhibition of ovulation by a novel progestogen (drospirenone)...., Eur contracept. Reprod. Health Care 5: 16-24 (2000)) ° In addition, TAUBERT, H.-D. and KUHL, H. (Kontrazeption mit Hormonen, editors Taubert, H.-D. et al., Georg Thieme Verlag Stuttgart/New York (1995), p. 160 ) shows irregularities in the 99919.doc 200534860 blood and low serum estrogen, in this case is B-base diol, or serum concentration of specific progestin is not related. SUMMARY OF THE INVENTION The purpose of the present disclosure is to indicate a natural estrogen-based hormonal contraceptive composition 'this composition achieves greater throughout the menstrual cycle than a natural estrogen-based typographic inhibiting composition. Contraceptive reliability, improve menstrual bleeding behavior and control side effects such as breast tenderness, headache, and libido changes. This object is achieved by the multi-phase contraceptive product of the invention - the first phase contains 2 daily doses of 3 mg of natural estrogen estradiol valerate, - the second phase contains 2 groups of daily dosage units, of which the first The group consists of a combination of 2 mg of estradiol valerate per dose and an ovulation inhibitor of at least two or three times the synthetic progesterone, and the second group consists of 17 daily dose units. 2 mg of estradiol valerate and a combination of ovulation inhibitors to >, monoterpene alpha or tetraterpene synthetic progesterone, _ third phase containing 2 daily dose units of 1 mg of estradiol pent The acid salt, - and the other phase contains 2 parts | a daily dosage unit of a pharmaceutically acceptable placebo. A preferred embodiment of the invention is a dimethicone, drospirenone or at least two times the amount of a progestin known as an ovulation inhibitor as an active agent. The multiphase product of the invention is particularly suitable for oral administration, but may also be administered intravaginally, 99919.doc 200534860 parenterally, including topical, and enteral, intranasal, buccal or sublingual. The oral cavity is prepared by using a conventional solid or liquid carrier or diluent and a dosage form suitable for the administration of the dosage form of the drug, in the form of a known product, a coated ingot, a sugar-coated tablet or Hard gelatin capsules are preferably administered orally. ▲ The present invention will now be described by way of examples. In this regard, it is particularly clarified that contraceptive guilty women's periodic bleeding behavior and tolerance to the regimen. Contraceptive reliability Contraception can be determined by using the m small, estriol and pregnancy values. Hoogland scores are shown. In this case, the pregnancy-serum concentration was determined by the date of the radioimmunoassay f in the period of the period and the number of times (10) (four) of the blessing fraction 6) and the undisrupted follicles only (H〇〇gland score 5). Cycle Stability Cycle stability is assessed based on the type of bleeding recorded per cycle. Special attention is paid to irregular bleeding (spots or breakthrough bleeding) in this regard. The way of recording is standardized. Analyze the data in an illustrative manner. Tolerance X-resistance is based on subjective perception, such as headache, depression, breast tenderness, gastrointestinal discomfort (nausea/vomiting), edema, and altered libido. [Examples] Using Example 1 The following plan was used: 1 to 2 days 3 mg estradiol valerate / day 3 to 7 days 2 mg estradiol valerate / day + 2 mg diengestrolonitrile / day 99919 .doc 200534860 8 to 24 days 2 mg estradiol valerate / day + 3 mg dimethacene nitrile / day 25 to 26 days 1 mg estradiol valerate / day 27 to 28 days placebo study is 93 Women aged between 18 and 35 years old. Each period of administration took 3 cycles, but only the 2nd and 3rd cycles were observed. In the second cycle (main target variable), 3 out of 93 (3.23%) were typographically printed, and 2 out of 92 in the third cycle ovulated.

Therefore, it can be recorded that according to the administration scheme of the present invention, 96.77% of ovulation inhibits reliability. At the same time, it was found that the administration scheme of the present invention is well tolerated. Use Example 2 1 to 2 days 3 mg estradiol valerate / day 3 to 7 days 2 mg estradiol valerate / day + 3 mg dimethacene nitrile / day 8 to 24 days 2 mg estradiol pent Acid salt / day + 4 mg dimetheronitrile / day 25 to 26 days 1 mg estradiol valerate / day 2 7 to 28 days placebo, study was conducted in 93 women aged 18 to 35 years. Each period of administration is 〇 cycle, but only the second and third cycles are observed. In the second cycle (main target variable), 2 out of 93 people (2 · %) were typographically printed, and 2 out of 92 people in the third cycle were typographically printed. 97.85% of ovulation was recorded, so it can be recorded as according to the present invention. Reliability. At the same time, it was found that the present invention is well tolerated. The two use cases can be used to record the appropriate rows of 999 丨9.doc 10 200534860 97.85% A 96.77% 〇PiersonRAetal.,, OrthoEvra/ /Evra versus oral contraceptives: follicular development...

Fertil· Steril 80 (1), pp. 34-42 (2003) recently conducted studies using conventional ovulation inhibitors, showing that even a reliable and safe product that is widely used over a long period of time still has a certain percentage of ovulation. In the second treatment cycle, it may be observed that typographical '14% (3 out of 22) ovulation, for example, in a three-phase oral contraceptive containing levonorgestrel Novo _'s single-phase oral contraceptives have ovulation (6 out of 25), with 16% (4 out of 25) of three-phase oral contraceptives containing norgestimate. Therefore, the product of the present invention has obvious value and has higher reliability than those described by Pierson et al.

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Claims (1)

200534860 X. The scope of application for patents·· 1 · A kind of eclipse for the use of contraception 4 * jin yi 3 yin phase, which is characterized by the fact that the first phase contains 2 parts of bismuth valerate per ton, and the early 33⁄4 gram of natural The estrogen estradiol Gedi two-phase contains 2 groups daily, and the daily dose of the individual is a 5-digit houser estradiol valerate and at least two or three times the ovulation. Inhibitors - 1 formed by a combination of & progesterone, short by 17 mg per unit dose of 2 mg of estradiol citrate to >, three or four times the amount of "inhibitor The synthetic adduct forms a third phase containing 2 parts of estradiol valerate per dose unit, and a phase 3 pharmaceutically acceptable placebo per dose unit 0 2 · according to the "patent range The multiphase product of item i is characterized in that the synthetic pregnancy active ingredient is dienQgest, drGspiren_ or at least one times the amount of known typographic inhibitor. 99919.doc 200534860 VII. Designation of Representative Representatives (1) The representative representative of the case is: (none) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please reveal the characteristics that best show the invention. Chemical formula: (none) 99919.doc